Tumors tend to develop resistance to chemotherapy drugs over time. To overcome such drug resistance, doctors routinely prescribe different chemotherapy drugs at different stages of treatment. Therefore, cancer patients will have a higher probability of surviving their particular cancer as the number of novel anti-cancer drugs increases.
Sirolimus, also known as rapamycin, is a lipophilic macrolide antibiotic initially developed for use as an immune suppressor for transplant patients. It was subsequently used in a drug coating for coronary artery stents, where it functions to reduce restenosis following angioplasty by inhibiting smooth muscle cell proliferation. Sirolimus also has anti-tumor activity. See U.S. Pat. No. 4,885,171.
Derivatives of sirolimus have also been found to be effective for treating certain cancers. For example, everolimus, a sirolimus derivative, is an approved drug for treating both advanced kidney cancer and inoperable progressive or metastatic pancreatic neuroendocrine tumors.
Umirolimus (40-alkoxyalkyl rapamycin or biolimus A9), a highly lipophilic derivative of sirolimus, is 10 times more lipophilic as compared to other “limus” family compounds such as sirolimus and everolimus. See J. Med. Chem. 2000, 43:2922-2928. This property gives umirolimus a higher affinity for lipid-rich cell membranes. However, such a high lipophilicity makes umirolimus less soluble in typical pharmaceutical preparations. Consequently, special formulations of umirolimus are needed to effectively deliver it to the site of a tumor.
The need exists for developing new chemotherapy agents containing umirolimus formulations which are soluble and stable in aqueous solution, have prolonged circulation after administration, and have tumor targeting capability.